ABSTRACT Indolent non-Hodgkin lymphomas are incurable diseases, and require intermittent and often morbid and expensive therapy during their prolonged natural history. Lower intensity and better-tolerated, cost-effective treatment strategies are needed for these patients. Low vitamin D levels at diagnosis of indolent lymphomas are strongly associated with inferior outcomes to treatment. Standard therapy for low tumor burden, indolent lymphoma includes a single agent monoclonal antibody (rituximab). In this proposal, we will complete a double-blind, placebo- controlled randomized trial evaluating if vitamin D supplementation with 2000IU oral tablets daily for three years improves the progression-free survival of patients with indolent lymphoma treated with single agent rituximab. Stratification factors for randomization will include histology and FL-IPI prognostic score. The primary endpoint of the trial is progression-free survival over three years; secondary endpoints include response at 13 weeks, and overall survival. Planned subset analyses include follicular lymphoma histology and female sex. With 210 randomized patients, we will have 80% power to detect a HR = 0.55 at a two sided alpha = 0.05 level of significance. This clinical trial will be coordinated at the University of Rochester Wilmot Cancer Institute, and six expert lymphoma centers from the Lymphoma Epidemiology of Outcomes (LEO) Consortium will participate. We will leverage this LEO consortium for tumor banking and prospective patient-reported outcomes of enrolled patients. We will also identify if baseline and/or restaging serum vitamin D levels predict subgroups of patients for whom Vitamin D supplementation is particularly effective or particularly ineffective. Finally, since there is evidence to suggest that response to oral vitamin D supplementation may be dependent upon specific genotypes of the Vitamin D receptor (VDR) and vitamin D binding protein (DPB), we will utilize whole exome sequencing to determine whether vitamin D-related germline variations are critical determinants of outcome in the context of vitamin D supplementation of patients with indolent lymphoma. Our aims the defining threshold levels of vitamin D where supplementation is most effective and the impact of germline polymorphisms on outcome will inform future trial designs and contribute to mechanistic understanding. Demonstrating a benefit to vitamin D supplementation in this randomized trial would rapidly change standard of care in the most common presentation of indolent lymphoma, and provide a low-risk, well-tolerated, inexpensive option delaying the time to morbid treatments.